17-Hydroxy-3-oxo-17{60 -pregna-4,7-diene-21-carboxylic acid-lactone, 4{40 ,5{40 -dihydrospiro{8 androsta-4,7-diene-17,2{40 (3{40 H)-furan{9 -3-one, and intermediates thereto

ABSTRACT

Preparation of DCA-blocking 17-hydroxy-3-oxo-17 Alpha -pregna4,7-diene-21-carboxylic acid gamma -lactone and 4&#39;&#39;,5&#39;&#39;dihydrospiro(androsta-4,7-diene-17,2&#39;&#39;(3&#39;&#39;H)-furan)-3-one from estrogenic intermediates is disclosed.

United States Patent Brown [4 1 May 27, 1975 l 7-HYDROXY-3-OXO 17a-PREGNA-4,7- DIENE-Zl-CARBOXYLIC AClD-LACTONE, 4 ',5 '-DIHYDROSPIRO[ANDROSTA-4,7- DlENE-l7,2'(3'H)-FURAN]-3-ONE, AND INTERMEDIATES THERETOEdward A. Brown, Glenview, Ill.

Assignee: G. D. Searle & Co., Chicago, 111.

Filed: Mar. 8, 1974 Appl. No.: 449,276

Inventor:

U.S. Cl ..260/239.55 R, 260/239.57,

. 260/397.1; 424/238 Int. Cl. C07c 173/00 Field of Search 260/239.57

[56] References Cited UNITED STATES PATENTS 3,787,394 l/l974 Anh et a1260/239.55 R

Primary ExaminerElbert L. Roberts Attorney, Agent, or Firm-John M. Brown7 Claims, No Drawings 17-HYDROXY-3-OXO-17a-PREGNA-4,7-DIENE-2l-CARBOXYLIC AClD-LACTONE, 4 ',5 -DIHYDROSPIRO[ANDROSTA-4,7-DIENE- I17,2'(3'H)-FURAN]-3-ONE( AND INTERMEDIATES wherein Z represents carbonylor methylene. Equivalent to the enformulated compounds, for the purposesof this invention, are the hydroxy acid and salts and esters thereofpreparable by procedures well-known in the art and having the formula inwhich M represents hydrogen, alkali metal, alkaline earth metal/2,ammonium, or lower alkyl. Those skilled in the art will recognize thatthe term alkaline earth metal/2 reflects the fact that such metals aredivalent,

whereas the other substituents represented by M are monovalent; andwhen, for example, M represents Ca/2, the contemplated salt isconventionally depicted thus The products of this invention are usefulby reason of their valuable biological properties. Thus, for example,they are diuretic: They reverse the effect of desoxycorticosteroneacetate (DCA) on urinary sodium and potassium.

The capacity of the instant compounds to reverse the renal electrolyteeffects of DCA is evident from the results of a standardized test forthis property carried out in rats substantially as described by C. M.Kagawa in chapter 34 of volume ll of Evaluation of DrugActivitieszPharmacometrics by D. R. Laurence and A. L. Bacharach.Details of such testing are described in US. Pat. Nos. 3,422,096 and3,622,631. The median effective dose of the representative product ofExample 1C hereinafter in tests carried out substantially as describedin the aforesaid patents was 0.52 mg. administered subcutaneously.

Those skilled in the art will recognize that observations of activity instandardized tests for particular biological effects are fundamental tothe development of valuable new drug products, both veterinary andhuman.

Preparation of the lactone and cyclic ether of this invention proceedsby heating a steroid of the formula with acetic anhydride and acetylchloride in a nitrogen atmosphere to produce an enol acetate of theformula CH COO which is contacted in the absence of incident light undernitrogen, using diethyl ether and methanol as solvents, with sodiumtetrahydroborate(l-) and water. The resultant 5,7-dien-3B-ol 1 isconverted to the desired lactone or cyclic ether via Oppenaueroxidation. In the three formulas immediately preceding, Z retains themeaning assigned above. Compounds of the latter two formulas, inaddition to being useful as intermediates, are estrogenic.

The following examples described in detail compounds illustrative of thepresent invention and methods which have been devised for theirpreparation. It will be apparent to those skilled in the art that manymodifications, both of materials and of methods, may be practicedwithout departing from the purpose and intent of this disclosure.Throughout the examples hereinafter set forth, temperatures are given indegrees centigrade and relative amounts of materials in parts by weight,except as otherwise noted.

EXAMPLE 1 A. A mixture of 1 parts ofl7-hydroxy-3-oxo-l7apregna-4,6-diene-2l-carboxylic acid y-lactone (US.Pat. No. 2,900,383), 550 parts of acetic anhydride, and 1 10 parts ofacetyl chloride is heated at 9095 in a nitrogen atmosphere for 17 hours,then cooled first to 25 and finally to 5. The crystalline precipitatewhich forms is filtered off, washed with 160 parts of ice-cold methanol,and recrystallized from methanol to give 3B-acetoxy-17-hydroxy-l7a-pregna-3 ,5 ,7-triene-2 l carboxylic acid'y-lactone melting at 194-l97.

B. To a solution of 382 parts of 3B-acetoxy- 17-hydroxy- 1 7a-pregna-3,5 ,7-triene-2 l -carboxylic acid y-lactone in 28,000 parts of diethylether and 56,000 parts of methanol, protected from incident light andunder a nitrogen atmosphere, is added, with stirring, a solution of 700parts of sodium tetrahydroborate( l-) in 16,000 parts of methanol and6,000 parts of water. Stirring is continued for 3 /2 hours, whereuponthe reaction mixture is poured into 300,000 parts of cold water. Theresultant mixture is extracted with ethyl acetate. The ethyl acetateextract is washed with water, dried over anhydrous sodium sulfate, andstripped of solvent by vacuum distillation. The residue, onrecrystallization from methanol, affords 313,17- dihydroxy-17a-pregna-5,7-diene-2 l -carboxylic acid 'y-lactone melting at l93l98.

C. A solution of 342 parts of3,8,17-dihydroxyl7a-pregna-5,7-diene-2l-carboxylic acid 'y-lactone in13,500 parts of dry toluene and 2,300 parts of cyclohexanone is heatednearly to boiling, with stirring under nitrogen. A solution of 342 partsof aluminum isopropoxide in 13,500 parts of dry toluene is thereuponintroduced, and the reaction mixture is then brought quickly to boilingunder reflux and maintained thereat for minutes, stirring beingcontinued throughout. The mixture is then cooled to 25 and diluted with1,450 parts of a saturated aqueous solution of Rochelle salt. Themixture thus obtained is steam distilled until the distillate is clear,whereupon the distilland is extracted with dichloromethane. Thedichloromethane extract is washed with water, dried over anhydroussodium sulfate, and stripped of solvent by vacuum distillation. The oilyresidue is crystallized from ethyl acetate to givel7-hydroxy-3-oxo-l7a-pregna- 4,7-diene-2l-carboxylic acid y-lactone.

' EXAMPLE 2 A. Substitution of 105 parts of,4,5-dihydrospiro[androsta-4,6dienel 7,2 3 H )-furan ]-3-one [J. Med.Chem., 6, 6l7 (1963)] for the l7-hydroxy-3-oxo- 4 l7a-pregna-4,6-diene-2l -carboxylic acid y-lactone called for in Example 1A affords, by theprocedure there detailed, 3B-acetoxy-4,5-dihydrospiro[androsta-3,5,7-triene-17,2(3H)- furan].

of 328 parts of wherein Z represents carbonyl or methylene.

2. A compound according to claim 1 which is 17-hydroxy-3-oxo-17a-pregna-4,7-diene-2 l-carboxylic acid y-lactone.

3. A compound according to claim 1 which is 4',5-dihydrospiro[androsta-4,7-dienel 7,2 3 'H )-furan]- 3-one.

4. A compound of formula wherein Z represents carbonyl or methylene.

5. A compound according to claim 4 which is 38,17- dihydroxyl7a-pregna-5 ,7-diene-2 l -carboxylic acid 'y-lactone.

6. A compound according to claim 4 which is 4',5-dihydrospiro[androsta-5 ,7-dienel 7,2 3 'H )-furan]- 3,8-01.

7. 3/3-Acetoxy-4 ,5 -dihydrospiro androsta-3,5,7-triene-l7,2(3'H)-furan].'

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,886,1i6

DATED May 27 1975 INVENTOMS) 1 Edward A. Brown It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Title, "ACID--LAC'IOI\IE' should read ACID y-LACTONE Abstract, "17.2'"should read 17,2

Column 1, line 2, ACID-LAC'IONE" should read -ACID Y-LACTONE--.

Column 1, line 4, ONE(" should read ONE,

vColumn i, line 20, "U'-" should read i',5'-

Signed and Sealed this twen ty-eight D ay Of October 1 975 [SEAL] Attest:

RUTH C. MASON C. MARSHALL DANN Attesn'ng Officer Commissioner nj'larentsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 which is17-hydroxy-3-oxo-17 Alpha -pregna-4,7-diene-21-carboxylic acid gamma-lactone.
 3. A compound according to claim 1 which is4'',5''-dihydrospiro(androsta-4,7-diene-17,2''(3''H)-furan)-3-one.
 4. Acompound of formula
 5. A compound according to claim 4 which is 3 Beta,17-dihydroxy-17 Alpha -pregna-5,7-diene-21-carboxylic acid gamma-lactone.
 6. A compound according to claim 4 which is4'',5''-dihydrospiro(androsta-5,7-diene-17,2''(3''H)-furan)-3 Beta -ol.7. 3 Beta -Acetoxy-4'',5''-dihydrospiro(androsta-3,5,7-triene-17,2''(3''H)-furan).